Daphne Atlas, Ph.D. M.Sc, Professor of Neurochemistry, Dept. of Biological Chemistry, Institute of Life Sciences, The Hebrew University of Jerusalem
Autism spectrum disorder (ASD) is a heterogeneous disorder initiated early in development and characterized by abnormal social communication. Autistic characteristics are exhibited by individuals affected by a multitude of genetic syndromes, one of them being Timothy syndrome (TS), which is caused by a point mutation* in the calcium channel CaV1.2. TS is a multisystem disorder also characterized by cardiac arrhythmias.
We are studying two TS mutations, G406R and G402S, that occur in CaV1.2. These mutations cause an abnormal calcium overload# leading to a cardiac arrhythmia. Surprisingly, according to our study, only the G406R mutation is associated with autism spectrum disorder (in 4 out of 5 patients), whereas the G402S mutation is not associated with the disorder.
In our study, we investigated the effect of G406R single point mutations of the CaV1.2 gene on cellular processes that could lead to multifactorial diseases such as autism. It is known that CaV1.2 and other calcium channels induce gene expression†. Mutant calcium channels can lead to defects in long-term processes and thus to diseases such as neurological developmental disorders and psychiatric diseases (including schizophrenia, bipolar disorder and autism).
The researchers, led by Professor Daphne Atlas at the Hebrew University of Jerusalem’s Alexander Silberman Institute of Life Sciences, found that both the CaV1.2 TS mutants G406R and G402S activate gene expression programs (transcriptional activity‡) via the Ras/ERK/CREB pathway, similar to the non-mutated CaV1.2 channel. “We were surprised to discover that the autistic mutant G406R exhibits a constitutive§ transcriptional activation and the G402S mutation does not.” This difference might clarify why the G406R mutation is implicated in the development of autism while G402S is not,” shared Prof. Atlas.
The research findings of spontaneous activity of the G406R channel correlates with a constitutive activation of gene expression. This uncontrolled spontaneous gene activation, implies a possible mechanism. Indeed, the G406R and other calcium channel autistic mutants, as opposed to G402S, display a negative shift in voltage activation¶, which facilitates spontaneous activity. The shift in channel activation could potentially help predict and diagnose individuals with ASD. The spontaneous activity of the channel and subsequently spontaneous gene activation can be compared to a dripping faucet.
These findings imply that the TS G406R mutant exhibits deregulated channel activity at rest (i.e. without stimulation) and is likely to exhibit spontaneous and uncontrolled gene expression. Other channel mutants associated with long-term disabilities display similar shifts in channel activation kinetics.
“Further studies are required to establish whether the uncontrolled activity of the channel at rest, which is associated with uncontrolled activation of gene programs in the TS G406R mutant, is the underlying mechanism by which other mutated channels increase the risk for neurodevelopmental disorders in humans,” explained Prof. Atlas.
The study was published in ‘Progress in Neurobiology’. It is part of a PhD thesis by Evrim Servili and was done in collaboration with fellow HU colleagues, Drs. Michael Trus, Eilon Sherman and Julia Sajman.
Elevated basal transcription can underlie timothy channel association with autism related disorders. Servili E, Trus M, Sajman J, Sherman E, Atlas D. Prog Neurobiol. 2020 Aug; 191:101820. doi: 10.1016/j.pneurobio.2020.101820. Epub 2020 May 11. PMID: 32437834
This research was supported by the H. L Lauterbach Family Fund.
* Point mutation: a type of gene mutation, in which a single “letter” of the DNA is exchanged, added or deleted. In Timothy syndrome, a “letter” is exchanged.
# Calcium overload: calcium is essential for the contraction of heart muscle cells. A calcium overload, however, disrupts the electrical activity that controls the contractions of the heart muscle, leading to an irregular heartbeat (i.e. arrhythmias).
† Gene expression: a process by which the information stored in the DNA is converted into a functional product (e.g. a protein).
‡ Transcriptional activity: transcription is a step in the gene expression process, in which a (RNA) transcript of the information stored in the DNA is made; the transcript is then used to synthesise the final product. The transcription process can be affected by a wide variety of molecules.
§ Constitutive: a term used (in biology and chemistry) to describe the ongoing production or secretion of a molecule
¶ Voltage activation: voltage-gated calcium channels (such as CaV1.2) are activated by an increase in voltage (i.e. concentration of charged particles), also known as the depolarisation of a cell. A negative shift in voltage activation causes the channels to become active at a lower voltage, which can be reached more quickly; it therefore facilitates the spontaneous activity of the channels.
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